tbuckley/cabot-search huggingface dataset:
Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease
Authors: Ja Min Byun, Chang-Ki Min, Kihyun Kim, Soo-Mee Bang, Je-Jung Lee, Jin Seok Kim, Sung-Soo Yoon, Youngil Koh
Journal: Journal of Hematology & Oncology (2022)

Abstract Extramedullary multiple myeloma (EMD) is an aggressive subentity of multiple myeloma (MM) with poor prognosis. As more innovative therapeutic approaches are needed for the treatment of MM with EMD, we conducted this multicenter, non-randomized phase II trial of daratumumab in combination with dexamethasone, cyclophosphamide, etoposide and cisplatin (DARA-DCEP). A total of 32 patients (median age 59, range 35–73) were treated with DARA-DCEP. Based on the best response during the study, the complete remission (CR) rate was 35.5% and overall response rate (ORR) 67.7%. During the median follow-up of 11 months, the median progression-free survival (PFS) was 5 months and median overall survival (OS) 10 months. There were 7 long-term responders whose median PFS was not reached. The most common grade ≥ 3 hematologic AE was thrombocytopenia. The most common non-hematologic AE was nausea (22.6%), followed by dyspepsia, diarrhea and stomatitis (all 12.9%). Grade ≥ 3 daratumumab infusion-related reaction was noted in 9.7% of the patients. Except for the planned 30% dose adjustment in cycle 1, only 2 patients required DCEP dose reduction. This is one of the very few prospective trials focusing on EMD and we successfully laid grounds for implementing immunochemotherapy in MM treatment.
Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2
Authors: Patrick C. O'Leary, Huadong Chen, Yagmur U. Doruk, Tess Williamson, Benjamin Polacco, Andrew S. McNeal, Tanushree Shenoy, Nupura Kale, Julia Carnevale, Erica Stevenson, David A. Quigley, Jonathan Chou, Felix Y. Feng, Danielle L. Swaney, Nevan J. Krogan, Minkyu Kim, Morgan E. Diolaiti, Alan Ashworth
Journal: Cancer Research (2022)

Abstract Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a large-scale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense-mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in UPF2-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G1 following treatment with ATRi. UPF2 loss also reduced transcription–replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs. Significance: Loss of NMD proteins promotes resistance to ATR inhibitors in gastric cancer cells, which may provide a combination of therapeutic targets and biomarkers to improve the clinical utility of these drugs.
Impact of adherence to individual quality-of-care indicators on the prognosis of bloodstream infection due to Staphylococcus aureus: a prospective observational multicentre cohort
Authors: Francesc Escrihuela-Vidal, Achim J. Kaasch, Maja Von Cube, Siegbert Rieg, Winfried V. Kern, Harald Seifert, Kyoung-Ho Song, Chun-Hsing Liao, Robert Tilley, Hannah Gott, Matt Scarborough, Claire Gordon, Martin J. Llewelyn, Richard Kuehl, Laura Morata, Alex Soriano, Jonathan Edgeworth, Enrique Ruiz De Gopegui, Emmanuel Nsutebu, José Miguel Cisneros, Vance G. Fowler, Guy Thwaites, Joaquín López-Contreras, Gavin Barlow, Hugo Guillermo Ternavasio-De La Vega, Jesús Rodríguez-Baño, Luis Eduardo López-Cortés
Journal: Clinical Microbiology and Infection (2022)

To analyse the adherence and impact of quality-of-care indicators (QCIs) in the management of Staphylococcus aureus bloodstream infection in a prospective and multicentre cohort.Analysis of the prospective, multicentre international S. Aureus Collaboration cohort of S. Aureus bloodstream infection cases observed between January 2013 and April 2015. Multivariable analysis was performed to evaluate the impact of adherence to QCIs on 90-day mortality.A total of 1784 cases were included. Overall, 90-day mortality was 29.9% and mean follow-up period was 118 days. Adherence was 67% (n = 1180/1762) for follow-up blood cultures, 31% (n = 416/1342) for early focus control, 77.6% (n = 546/704) for performance of echocardiography, 75.5% (n = 1348/1784) for adequacy of targeted antimicrobial therapy, 88.6% (n = 851/960) for adequacy of treatment duration in non-complicated bloodstream infections and 61.2% (n = 366/598) in complicated bloodstream infections. Full bundle adherence was 18.4% (n = 328/1784). After controlling for immortal time bias and potential confounders, focus control (adjusted hazard ratio = 0.76; 95% CI, 0.59-0.99; p 0.038) and adequate targeted antimicrobial therapy (adjusted hazard ratio = 0.75; 95% CI, 0.61-0.91; p 0.004) were associated with low 90-day mortality.Adherence to QCIs in S. Aureus bloodstream infection did not reach expected rates. Apart from the benefits of application as a bundle, focus control and adequate targeted therapy were independently associated with low mortality.
Targeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises
Authors: I. Anestopoulos, S. Kyriakou, V. Tragkola, I. Paraskevaidis, E. Tzika, M. Mitsiogianni, M.V. Deligiorgi, G. Petrakis, D.T. Trafalis, S. Botaitis, A. Giatromanolaki, M.I. Koukourakis, R. Franco, A. Pappa, M.I. Panayiotidis
Journal: Pharmacology & Therapeutics (2022)
Epigenetic upregulation of Schlafen11 renders &amp;#x2028;WNT- and SHH-activated medulloblastomas sensitive to cisplatin
Authors: Satoshi Nakata, Junko Murai, Masayasu Okada, Haruhiko Takahashi, Tyler H Findlay, Kristen Malebranche, Akhila Parthasarathy, Satoshi Miyashita, Ramil Gabdulkhaev, Ilan Benkimoun, Sabine Druillennec, Sara Chabi, Eleanor Hawkins, Hiroaki Miyahara, Kensuke Tateishi, Shinji Yamashita, Shiori Yamada, Taiki Saito, Jotaro On, Jun Watanabe, Yoshihiro Tsukamoto, Junichi Yoshimura, Makoto Oishi, Toshimichi Nakano, Masaru Imamura, Chihaya Imai, Tetsuya Yamamoto, Hideo Takeshima, Atsuo T Sasaki, Fausto J Rodriguez, Sumihito Nobusawa, Pascale Varlet, Celio Pouponnot, Satoru Osuka, Yves Pommier, Akiyoshi Kakita, Yukihiko Fujii, Eric H Raabe, Charles G Eberhart, Manabu Natsumeda
Journal: Neuro-Oncology (2022)

Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma.SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo.High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells.High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.
The First FLASH Clinical Trial—The Journey of a Thousand Miles Begins With 1 Step
Authors: Lesley A. Jarvis, Rongxiao Zhang, Brian W. Pogue
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
Authors: Sonja I. Berndt, Joseph Vijai, Yolanda Benavente, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Karin E. Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F. Skibola, Lindsay M. Morton, Angela R. Brooks-Wilson, Lauren R. Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C. Anderson, Stephen M. Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M. Birmann, Paolo Boffetta, Paige M. Bracci, Paul Brennan, Elizabeth E. Brown, Laurie Burdett, Lisa A. Cannon-Albright, Ellen T. Chang, Brian C. H. Chiu, Charles C. Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V. Conti, David G. Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W. Ryan Diver, Ahmet Dogan, Christopher K. Edlund, Lenka Foretova, Joseph F. Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G. Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M. Habermann, Christopher A. Haiman, Corinne Haioun, Jonathan N. Hofmann, Theodore R. Holford, Elizabeth A. Holly, Amy Hutchinson, Aalin Izhar, Rebecca D. Jackson, Ruth F. Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N. Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K. Link, Corrado Magnani, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Alain Monnereau, Rebecca Montalvan, Kari E. North, Anne J. Novak, Kenan Onel, Mark P. Purdue, Kristin A. Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W. Sborov, Richard K. Severson, Tait D. Shanafelt, Martyn T. Smith, Alexandra Smith, Kevin W. Song, Lei Song, Melissa C. Southey, John J. Spinelli, Anthony Staines, Deborah Stephens, Heather J. Sutherland, Kaitlyn Tkachuk, Carrie A. Thompson, Hervé Tilly, Lesley F. Tinker, Ruth C. Travis, Jenny Turner, Celine M. Vachon, Claire M. Vajdic, Anke Van Den Berg, David J. Van Den Berg, Roel C. H. Vermeulen, Paolo Vineis, Sophia S. Wang, Elisabete Weiderpass, George J. Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R. Cerhan, Stephen J. Chanock, Susan L. Slager, Nathaniel Rothman
Journal: Leukemia (2022)
Fibrostenotic eosinophilic esophagitis phenotype is defined by a proliferative gene signature
Authors: Calies Menard‐Katcher, Cuining Liu, Matthew D. Galbraith, Taylor Benson, Cassandra Burger, Devin Dobias, Leigha Larsen, Carol O'Brien, Lisa A. Spencer, Glenn T. Furuta, Joanne C. Masterson
Journal: Allergy (2022)

Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease
Authors: Tobias Petzold, Zhe Zhang, Iván Ballesteros, Inas Saleh, Amin Polzin, Manuela Thienel, Lulu Liu, Qurrat Ul Ain, Vincent Ehreiser, Christian Weber, Badr Kilani, Pontus Mertsch, Jeremias Götschke, Sophie Cremer, Wenwen Fu, Michael Lorenz, Hellen Ishikawa-Ankerhold, Elisabeth Raatz, Shaza El-Nemr, Agnes Görlach, Esther Marhuenda, Konstantin Stark, Joachim Pircher, David Stegner, Christian Gieger, Marc Schmidt-Supprian, Florian Gaertner, Isaac Almendros, Malte Kelm, Christian Schulz, Andrés Hidalgo, Steffen Massberg
Journal: Immunity (2022)

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.
Multi-hit TET2 mutations as a differential molecular signature of oligomonocytic and overt chronic myelomonocytic leukemia
Authors: Nieves Garcia-Gisbert, Leonor Arenillas, David Roman-Bravo, Juan Jose Rodriguez-Sevilla, Concepción Fernández-Rodríguez, Sara Garcia-Avila, Patricia Velez, Joan Gibert, Lierni Fernández-Ibarrondo, Antonio Salar, Lourdes Florensa, Beatriz Bellosillo, Ana Ferrer, Xavier Calvo
Journal: Leukemia (2022)
Viral dynamics of the SARS-CoV-2 Omicron Variant among household contacts with 2 or 3 COVID-19 vaccine doses
Authors: Christopher Kandel, Yaejin Lee, Maureen Taylor, Andrea Llanes, Janine McCready, Gloria Crowl, Jeff Powis, Angel Xinliu Li, Altynay Shigayeva, Lily Yip, Kevin Katz, Robert Kozak, Samira Mubareka, Allison McGeer
Journal: Journal of Infection (2022)
REM sleep-active hypothalamic neurons may contribute to hippocampal social-memory consolidation
Authors: Han Qin, Ling Fu, Tingliang Jian, Wenjun Jin, Mengru Liang, Jin Li, Qianwei Chen, Xinyu Yang, Haoran Du, Xiang Liao, Kuan Zhang, Rui Wang, Shanshan Liang, Jiwei Yao, Bo Hu, Shuancheng Ren, Chunqing Zhang, Yanjiang Wang, Zhian Hu, Hongbo Jia, Arthur Konnerth, Xiaowei Chen
Journal: Neuron (2022)
Activation of the cGAS-STING pathway combined with CRISPR-Cas9 gene editing triggering long-term immunotherapy
Authors: Qianglan Lu, Ruiyue Chen, Shiyu Du, Chao Chen, Yongchun Pan, Xiaowei Luan, Jingjing Yang, Fei Zeng, Bangshun He, Xin Han, Yujun Song
Journal: Biomaterials (2022)
American College of Rheumatology/<scp>EULAR</scp> Remission Criteria for Rheumatoid Arthritis: 2022 Revision
Authors: Paul Studenic, Daniel Aletaha, Maarten de Wit, Tanja A. Stamm, Farideh Alasti, Diane Lacaille, Josef S. Smolen, David T. Felson
Journal: Arthritis & Rheumatology (2022)

In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean- and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the 2 sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria.We used data from 4 randomized trials comparing biologic disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared to the original threshold of 1 cm (Boolean1.0). We analyzed agreement between the Boolean- and index-based criteria (Simplified Disease Activity Index [SDAI] and Clinical Disease Activity Index [CDAI]) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire [HAQ] score ≤0.5) and radiographic nonprogression.Data from 2,048 trial participants, 1,101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared to Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes.Using the Boolean 2.0 criteria classifies more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardizing predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.
Robust Control Strategy of Gradient Magnetic Drive for Microrobots Based on Extended State Observer
Authors: Jiawei Lu, Yueyue Liu, Wentao Huang, Kaitao Bi, Yixin Zhu, Qigao Fan
Journal: Cyborg and Bionic Systems (2022)

Microrobots have great application potential in the biomedical field, to realize the precision and efficiency of microrobots in vivo is research focus in this field. Microrobots are accompanied by various disturbances in complex environment. These disturbances will affect the motion control of microrobots, resulting in the inability of the micromanipulation tasks to be completed effectively. To this end, a robust motion control method is proposed for precise path tracking of microrobots in this paper. The extended state observer (ESO) is used to estimate the total disturbances and uncertainties of the system. A path tracking controller is designed by combining sliding mode control (SMC) and disturbances compensation, which is used to eliminate the total disturbances of the system and realize the fast and accurate path tracking of microrobots. Finally, the path tracking experiments are implemented in the gradient magnetic field drive system. The experimental results show that the mean absolute error of the path tracking for microrobots in a simulated vascular structure is less than 14 μ m, and the root mean square error is less than 17 μ m by using the robust control method proposed in this paper. Compared with the traditional PID control method, it can better suppress external disturbances and uncertainties of the system and improve the path tracking accuracy of microrobots effectively. It shows stronger anti-interference ability and robustness.
Correction: Knockdown of SOX2OT inhibits the malignant biological behaviors of glioblastoma stem cells via up-regulating the expression of miR-194-5p and miR-122
Authors: Rui Su, Shuo Cao, Jun Ma, Yunhui Liu, Xiaobai Liu, Jian Zheng, Jiajia Chen, Libo Liu, Heng Cai, Zhen Li, Lini Zhao, Qianru He, Yixue Xue
Journal: Molecular Cancer (2022)
Automated clinical coding: what, why, and where we are?
Authors: Hang Dong, Matúš Falis, William Whiteley, Beatrice Alex, Joshua Matterson, Shaoxiong Ji, Jiaoyan Chen, Honghan Wu
Journal: npj Digital Medicine (2022)

Abstract Clinical coding is the task of transforming medical information in a patient’s health records into structured codes so that they can be used for statistical analysis. This is a cognitive and time-consuming task that follows a standard process in order to achieve a high level of consistency. Clinical coding could potentially be supported by an automated system to improve the efficiency and accuracy of the process. We introduce the idea of automated clinical coding and summarise its challenges from the perspective of Artificial Intelligence (AI) and Natural Language Processing (NLP), based on the literature, our project experience over the past two and half years (late 2019–early 2022), and discussions with clinical coding experts in Scotland and the UK. Our research reveals the gaps between the current deep learning-based approach applied to clinical coding and the need for explainability and consistency in real-world practice. Knowledge-based methods that represent and reason the standard, explainable process of a task may need to be incorporated into deep learning-based methods for clinical coding. Automated clinical coding is a promising task for AI, despite the technical and organisational challenges. Coders are needed to be involved in the development process. There is much to achieve to develop and deploy an AI-based automated system to support coding in the next five years and beyond.
Clinical usefulness of serum angiotensin converting enzyme in silicosis
Authors: J. Blanco-Pérez, Á. Salgado-Barreira, S. Blanco-Dorado, M.E. González Bello, A.C. Caldera Díaz, A. Pérez-Gonzalez, A. Pallarés Sanmartín, A. Fernández Villar, F.J. Gonzalez-Barcala
Journal: Pulmonology (2022)

Silicosis is an irreversible and incurable disease. Preventive measures to eliminate exposure are the only effective way to reduce morbidity and mortality. In such situations, having a biomarker for early diagnosis or to predict evolution would be very useful in order to improve control of the disease. The elevation of serum angiotensin-converting enzyme (sACE) in silicosis has been described in previous studies, although its relationship with severity and prognosis is not clear.